Introduction : Yawning is a
behavioral pattern that has gained increasing
recognition in this last quarter of the
twentieth century. The easiness with which this
motor act may be induced, or modulated in
frequency by different pharmacological agents in
laboratory animals, particularly among rodents,
has brought to focus a complex set of
neurotransmitters and hormonal mechanisms
underlying yawning behavior.
It has been suggested that regulation of
yawning is partly the result of an interaction
between dopaminergic and cholinergic influences
on the central yawning pattern generator. The
fine details and localization of these
interactions in the central nervous system have
not been entirely worked out. Some authors
believe that dopaminergic induction of yawning
results from activation of low threshold
postsynaptic receptors exciting yawning, while
others suggest it is due to D2 autoreceptors
restraining the dopaminergic inhibitory
influences on yawing, thus disinhibiting
cholinergic yawn-excitatory pathways. There is
practically general agreement in that muscarinic
cholinergic antagonists counteract yawning,
whatever the pharmacological tool used to induce
it (ACTH physostigmine or pilocarpine,
apomorphine or other dopamine agonists). These
results suggest that the cholinergic link in
yawning regulation is downstream in relation to
the dopaminergic one.
In a previous
paper in this same journal we reported the
development of two inbred sublines of
Sprague-Dawley rats which differ significantly
in spontaneous mean yawning frequency (MYF): one
of them yawns at a low frequency (LY); the other
at a higher rate (HY). The prescrit report is an
attempt to identify the neural substrates of
this genetic difference in spontaneous yawning
frequency between HY and LY Sprague-Dawley rats,
by comparing their sensitivities to well known
dopaminergic and cholinergic yawn-inducing
drugs. [...]
Discussion : The results reported
above show that two sublines of Sprague-Dawley
rats which differ in their spontaneous yawning
frequencies also differ in their responses to
drugs with well known yawn-inducer
activities.
It is known that the concentrations and
turnover rates of several neurotransmitters, the
activities of their synthesizing or degradative
enzymes and their receptor densities in the
brain show genetic variations . Durkin et al.
have suggested that some changes in regional
neurotransmitter activities in the brain might
be due to primary differences in their
underlying genetic mechanisms, whereas other
might be secondary to imbalances in
neurotransmitter interactions. Strain
differences in behavioral expression or in
sensitivity to drugs may be one major
consequence of these changes.
Elicitation of yawning is mainly the result
of an interaction, somewhere in the brain,
between inhibitory dopaminergic and excitatory
cholinergic influences on the built-in motor
program for yawning. Yawning induced by low
doses of apomorphine or other DA agonists has
most generally been interpreted as the result of
their selective action on low-threshold DA
autoreceptors regulating impulse discharge,
synthesis and release of the neurotransmitter .
Other authors have postulated that this effect
could be due to postsynaptic excitatory DA2,
receptors . On the other hand, higher doses of
DA agonists decrease yawning by acting on high
threshold postsynaptic DA yawn-inhibitory
receptors.
In our previous
paper we had advanced the idea that HY rats
may have an increase in cholinergic tone,
understood as a direct and general effect,
intrinsic te, the cholinergic system as a whole,
or as an indirect and more particular
phenomenon, consecutive to a decrease in tonic
DA inhibitory activity, and therefore restricted
only to cholinergic pathways subject to
dopaminergic restraining control. In the case of
a primary difference affecting the cholinergie
system as a whole, different sensitivities to
cholinergic drugs, with no changes or smaller
ones in the response to doparninergic drugs, may
be present when comparing HY and LY rats. The
alternative hypothesis, that the, primary
genetic influences modifying yawning behavior in
these two sublines are exerted on dopaminergic
pathways may lead to differences in sensitivity
both to doparninergic drugs and secondarily to
cholinergic drugs.
The results obtained with APO and (- )3PPP,
point to the latter alternative. Both drugs have
been demonstrated to act on dopamine receptors
and have been used to study the role of DA
pathways on yawning and other behavioral
patterns. In HY rats the yawning dose-response
curves traced with these dopaminergic agents are
shifted to the left in relation to those in LY
animals, indicating higher DA sensitivity in the
former group. This suggests that the primary
genetic difference between HY and LY rats is a
decrease in the synthesis and/or release of
dopamine in the former subline when compared
with the latter. If this interpretation were
correct, postsynaptic cholinergic neurones,
partially disinhibited, would increase their
activity, releasing more ACh and thus increasing
MYF. The chronic increase in ACh might lead, as
a secondary effect, to a diminution in
sensitivity of muscarinic cholinoceptive
receptors related to the yawning central pattern
generator. We have tested this possibility by
the use of pilocarpine, a well known muscarinic
agonist and yawn-inducer .
We expected a diminution in
pilocarpine-induced yawning in HY rats but our
above described results do not agree with this
prediction: no différences in
pilocarpine-induced yawning responses are
evident between HY and LY rats . The high
turnover of ACh-esterase in the CNS could
explain that although more ACh may be released
in HY rats the steady average concentration of
the neurotransmitter in synaptic space would not
increase enough to determine changes in
postsynaptic receptors sensitivity. At this
point it seems interesting to comment that
Overstreet has recently shown differences in
muscarinic responses between Flinders-sensitive
(FSL) and Flinders-resistant (FRL) lines of
rats, differences that do not necessarily
correlate with changes in receptors.
Nevertheless other results reported here show
significant differences between the two sublines
(HY and LY) in regard to physostigmine-induced
yawning. Higher doses of this drug (a
competitive inhibitor of AChE) are needed to
induce yawning in HY rats. It is a well known
fact that competitive enzyme inhibitors are less
effective when their natural enzyme substrate is
increased. The lower yawn-inducing effect of
physostigmine in HY rats could be understood as
due to a higher basal concentration of ACh as
compared with LY animals.
In summary, the whole set of our results
with yawn-inducing dopaminergic and cholinergic
drugs suggest that the primary genetic
différence between the HY and LY
Sprague-Dawley sublines seems to affect the
activity of dopaminergic inhibitory pathways
that normally restrain yawning
frequency.
BIBLIOGRAPHIE
Eguibar
JR et Moyaho A Inhibition of grooming by
pilocarpine differs in high-and low yawning
sublines of Sprague-Dawley rats. Pharmacoology
Biochemistry and Bebavior 1997; 58: 2
317-322
Eguibar JR et
al Behavioral differences between
selectively bred rats: D1 versus D2 receptors in
yawning and grooming Pharmacology, Biochemistry
and Behavior 2003; 74; 827Ð832
Moyaho A
et al Induced grooming transitions and open
field behaviour differ in high and low-yavning
sublines of Sprague-Dawley rats. Anim Behav
1995; 50 ; 61-72
Urba-Holmgren R,
Trucios N, Holmgren B, Eguibar JR, Gavito A,
Cruz G, Santos A Genotypic dependency of
spontaneous yawning frequency in the rat Behav
Brain Res 1990 Oct 30;40(1):29-35
Urba-Holmgren R,
Santos A, Holmgren B, Eguibar JR Two inbred
rat sublines that differ in spontaneous yawning
behavior also differ in their responses to
cholinergic and dopaminergic drugs Behav Brain
Res 1993 Sep 30;56(2):155-9
Urba-Holmgren
R, Gonzalez RM, Holmgren B Is yawning a
cholinergic response? Nature 1977 May 19 267
(5608): 261-2 et commentaires Cholinergic link
in yawning A Cowan Nature 12/01/78 271
p187-188
